The present invention relates to methods and compositions for the treatment of Central Nervous System (CNS) disorders, including but not limited to Tourette Syndrome, in adults and children. The methods of the present invention comprise the utilization of pharmaceutical compositions to patients who are free of symptoms of cardiac disease and who have not been treated with drugs which cause hypotensive effects, such as nitrites and nitrates.
Tourette Syndrome (TS) is an autosomal dominant neuropsychiatric disorder affecting up to one person in 2,500 and is characterized by a range of neurological and behavioral symptoms. Such symptoms include: (A) the presence of both motor and vocal tics at some time during the illness, although not necessarily concurrently; (B) the occurrence of quasi-daily tics throughout a period of time exceeding one year; (C) variance in the clinical phenomenology of the tics; and (D) marked distress or significant impairment in social, occupational, or other important areas of functioning. Patients with TS also often suffer from co-morbid disorders such as Obsessive-Compulsive Disorder (OCD), Attention-Deficit Hyperactivity Disorder (ADHD), anxiety disorders, mood disorders, and panic disorders.
Tics experienced by a sufferer of TS can be transient or acute, and simple or complex. Motor tics generally include eye blinking, nose twitching, grimacing, muscle tensing, hopping, touching objects or others, and rapid jerking of any part of the body. Vocal or phonic tics typically include coughing, spitting, grunting, barking, hissing, sucking sounds, gurgling, screeching, whistling, palilalia, echolalia, and coprolalia.
The etiology and pathophysiology of TS are currently unknown. However, pharmacological and metabolic evidence suggests the involvement of several neurochemical systems, such as the dopaminergic, noradrenergic, GABAergic, and serotonergic mechanisms for example, and implicates neurotransmission dysfunction with the disorder.
Historically, attempts at treating TS by psychotherapeutic and behavior modification approaches were not encouraging in terms of dramatic, lasting improvement. Thus, the pursuit of behavioral strategies for decreasing the occurrence of tics has diminished. Current treatment of TS includes the administration of medications which are prescribed for neurotransmitter disorders. For example, neuroleptic drugs (i.e. those which reduce the amount of dopamine in the CNS) such as haloperidol, pimozide, fluphenazine, and chloropromazine have been administered to TS patients with success, but with side effects such as tardive dyskinesia, akinesia, increased appetite and weight gain, amenorrhea, Q and T wave changes, hypotension, and impotence. Other drugs such as clonidine (an antihypertensive), clonazepam (an anticonvulsant), and various antidepressants have been used to treat TS symptoms, but also induce side effects in the patient such as, for example, impotence.
Moreover, compounds that modulate activity of various receptors have been suggested as treatment due to a decreased number of receptors in the brains of patients suffering CNS disorders. (Cosford et al., U.S. Pat. No. 5,868,473 and Kerrigan et al., U.S. Pat. No. 5,767,116). Additionally, nicotine pharmacology has been suggested in suppressing TS. (Bencherif et al., U.S. Pat. No. 5,731,314). It has also been suggested that TS is caused by the supply of tryptophan to the brain, and TS symptoms have been treated by regulating the supply of tryptophan to the brain. (Richardson et al., U.S. Pat. No. 5,670,539).
Stimulants such as methylphenidate, dextroamphetamine, and pemoline may be prescribed for hyperactivity and ADHD, but often lead to an increase in the tics in TS. Antidepressants such as fluoxetine and clomiprimine are often prescribed to treat OCD symptoms. However, such antidepressants may also induce side effects such as muscle weakness, seizures, constipation, and impotence.
Although other pharmacological methods of treatment of TS are available, such methods have not proven to be highly satisfactory and can be accompanied by severe side-effects. What is needed is an improved method for the treatment of CNS disorders, including but not limited to Tourette Syndrome, without the induction of side effects in the patient such as, for example, impotence.
The present invention relates to methods and compositions for the treatment of Tourette Syndrome and other central nervous system disorders in adults and children. The methods of the present invention comprise the utilization of pharmaceutical compositions to patients who have symptoms of TS, but who are otherwise free of symptoms of cardiac disease and who have not been treated with drugs which cause hypotensive effects, such as nitrites and nitrates. The compositions comprise quinolinones, including derivatives and purified enantiomers thereof. Quinolinones are also known as quinolones and oxo-quinolines.
It is not intended that the present invention be limited by the nature of the derivative. In one embodiment, the quinolinones derivative is cilostazol (6-[4-(1-cyclohexyl-1-H-tetrazol-5-yl)butoxyl]-3,4-dihydro-2(1H)-quinolinone; 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydrocarbostyril; 6-[4-(1-cyclohexyl-5-tetrazoyl)butoxy]-1,2,3,4-tetrahydro-2-oxoquinoline).
In yet other embodiments, metabolites of cilostazol are contemplated for use in the methods of the presently claimed invention. Metabolites of cilostazol include, but are not limited to monohydroxycilostazol, monohydroxydehydrocilostazol, 3,4-dihydro-6-hydroxy-2(1H)-quinolinone, their conjugates and dehydrocilostazol.
In one embodiment, the present invention contemplates halogenated quinolinones (e.g., fluoroquinolinone). In a preferred embodiment, the quinolinone is a thioquinolinone or a sulphinyl or suphonyl derivatives thereof. In one embodiment, the halogenated quinolinone is flosequinan (7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone). In a preferred embodiment, an enantiomer of flosequinan is used.
In one embodiment, the present invention contemplates a method, comprising: a) providing: i) an adult or child with symptoms of a Central Nervous System (CNS) disorder, and ii) flosequinan; and b) administering said flosequinan to said adult or child. It is not intended that the present invention be limited to symptoms of Tourette Syndrome (TS). A variety of such symptoms are contemplated, including but not limited to, motor and vocal tics. In one embodiment, the present invention contemplates administering said flosequinan to said adult or child under conditions such that frequency and/or severity of tics of said adult or child is diminished.
In another embodiment, the method comprises providing: i) an adult or child with Tourette Syndrome, and ii) flosequinan; and introducing said flosequinan to adult or child (e.g. such that the symptoms of Tourette Syndrome of said adult or child are reduced).
In another embodiment, the present invention contemplates a method, comprising: a) providing: i) a male or female with symptoms of Tourette Syndrome, and ii) a composition comprising a quinolinone selected from the group consisting of a racemic mixture of flosequinan and an enantiomer of flosequinan; and b) administering said composition to said male or female (e.g. such that said symptoms are reduced). A variety of such symptoms are contemplated, including but not limited to, motor and vocal tics. In one embodiment, the present invention contemplates administering said composition to said adult or child under conditions such that frequency and/or severity of tics of said adult or child is diminished.
In a preferred embodiment, the male or female is an adult human and the oral dosage of flosequinan is in a single dose per day of up to approximately two hundred milligrams, and more preferably, between approximately ten to approximately seventy-five milligrams. In another preferred embodiment, flosequinan is administered in a single oral dose per day of between approximately one hundred and ten and approximately two hundred milligrams. In another preferred embodiment, the male or female is an adult human and the oral dosage of flosequinan is in three daily doses, before meals, each dose of up to approximately two hundred milligrams, and more preferably, between approximately ten to approximately seventy-five milligrams. In another preferred embodiment, flosequinan is administered in three oral doses per day, before meals, of between approximately one hundred and ten and approximately two hundred milligrams. In other embodiments said flosequinan is introduced cutaneously, by standard injection (e.g intravenously or intramuscularly), or intranasally.
In one embodiment, the method comprises a) providing: i) a subject (whether adult or child) suffering from symptoms of a CNS disorder who is free from cardiac disease; and ii) flosequinan; and b) introducing said flosequinan to said subject (e.g. such that said symptoms are reduced). A variety of such symptoms are contemplated, including but not limited to, motor and vocal tics. In one embodiment, the present invention contemplates administering said composition to said adult or child under conditions such that frequency and/or severity of tics of said adult or child is diminished. In another embodiment, said subject suffering from symptoms of a CNS disorder is not free from cardiac disease.
In another embodiment, the method comprises a) providing: i) a subject (whether adult or child) suffering from symptoms of a CNS disorder who is not being treated (and/or has not been treated in the past) with a drug that causes hypotensive effects, and ii) flosequinan; and b) introducing said flosequinan to said subject such that said symptoms are reduced. In another embodiment, said subject suffering from symptoms of a CNS disorder is being, or has been, treated with a drug that causes hypotensive effects.
In another embodiment, the method comprises a) providing: i) a subject (whether adult or child) suffering from symptoms of a CNS disorder who is not being treated (and/or has not been treated in the past) with a nitrite or nitrate, and ii) flosequinan; and b) introducing said flosequinan to said subject such that said symptoms are reduced. In another embodiment, said subject suffering from symptoms of a CNS disorder is being, or has been, treated with a nitrate or nitrite.
In yet other preferred embodiments, metabolites of cilostazol are contemplated for use in the methods of the presently claimed invention. Metabolites of cilostazol include, but are not limited to monohydroxycilostazol, monohydroxydehydrocilostazol, 3,4-dihydro-6-hydroxy-2(1H)-quinolinone, their conjugates and dehydrocilostazol.
In one embodiment, the method comprises a) providing: i) a subject (whether adult or child) suffering from symptoms of a CNS disorder; and ii) cilostazol; and b) administering cilostazol to the subject (e.g. such that said symptoms are reduced). A variety of such symptoms are contemplated, including but not limited to, motor and vocal tics. In one embodiment, the present invention contemplates administering said composition to said adult or child under conditions such that frequency and/or severity of tics of said adult or child is diminished.
In one embodiment, the method comprises a) providing: i) a subject (whether adult or child) suffering from symptoms of a CNS disorder who is not being treated (and/or has not been treated in the past) with a drug that causes hypotensive effects, and ii) cilostazol; and b) introducing said cilostazol to said subject such that said symptoms are reduced. In another embodiment, said subject suffering from symptoms of a CNS disorder is being, or has been, treated with a drug that causes hypotensive effects.
In another embodiment, the method comprises a) providing: i) a subject (whether adult or child) suffering from symptoms of a CNS disorder who is not being treated (and/or has not been treated in the past) with a nitrite or nitrate, and ii) cilostazol; and b) introducing said cilostazol to said subject such that said symptoms are reduced. In another embodiment, said subject suffering from symptoms of a CNS disorder is being, or has been, treated with a nitrate or nitrite.
It is not intended that the present invention be limited to the mode of administration. In one embodiment, cilostazol is administered orally. In another embodiment, cilostazol is administered cutaneously. In yet another embodiment, cilostazol is administered intranasally. In an alternative embodiment, cilostazol is administered through respiratory inhalation. In yet another alternative embodiment, cilostazol is administered by standard injection (e.g intravenously or intramuscularly).
In a preferred embodiment, the male or female is an adult human and the oral dosage of cilostazol is in a single dose per day of up to approximately two hundred milligrams, and more preferably, between approximately ten to approximately one hundred milligrams. In an even more preferred embodiment, cilostazol is administered in two oral doses per day of between approximately fifty and approximately one hundred milligrams. In another preferred embodiment, the male or female is an adult human and the oral dosage of cilostazol is in three daily doses, before meals, each dose of up to approximately two hundred milligrams, and more preferably, between approximately ten to approximately seventy-five milligrams, and even more preferably, between approximately fifty to approximately one hundred milligrams.
It is not intended that the present invention be limited to the treatment of certain patient groups. In one embodiment, the patient is an adult. In another embodiment, the patient is a child. In one embodiment, the patient is free from cardiac diseases including, but not limited to, congestive heart failure. In another embodiment, the patient has not been treated with a drug that causes hypotensive effects. In yet another embodiment, the patient has not been treated with nitrates or nitrites.
In another embodiment, the method comprises providing: i) an adult or child with Tourette Syndrome, and ii) a pharmaceutical composition comprising cilostazol; and introducing the pharmaceutical composition to the adult or child (e.g. such that the symptoms of Tourette Syndrome of said adult or child are reduced).
It is not intended that the present invention be limited by the nature of the formulation. In one embodiment, the present invention contemplates a formulation comprising a quinolinone or derivative thereof in a mixture comprising lactose.
The present invention is not limited by the degree of response by the subject. It is expected that the administration of quinolinones will reduce symptoms of CNS disorders, including but not limited to, motor and vocal tics associated with Tourette Syndrome.